Abstract
In G-CSF-mobilized hematopoietic SCT (HSCT), natural killer (NK) cells have a critical role in GVHD and GVL effects. However, regulation of NK cell response to G-CSF remains unclear. This study assayed G-CSF effects in both HSCT donors and NK-92MI cells. The donors who received G-CSF had significantly decreased NK cell cytotoxicity. Levels of phosphatidylinositol 3-kinase (PI3K) and phosphorylated (p)-Akt, but not mammalian target of rapamycin (mTOR), were downregulated in NK cells from G-CSF-injected donors. G-CSF also decreased cytotoxicity without affecting viability and NF-κB of NK-92MI cells. PI3K and p-ERK expression were also decreased in G-CSF-treated NK-92MI cells, and their inhibitors, wortmannin and PD98059, respectively, both enhanced the downregulation of cytotoxicity. These effects were accompanied by decreased expression of a cytotoxicity-related gene, triosephosphate isomerase (TPI). Wortmannin, but not PD98059, enhanced the downregulation of TPI in G-CSF-treated NK-92MI cells, indicating a correlation between PI3K and TPI. We conclude that G-CSF-impaired NK cell cytotoxicity may accompany PI3K/Akt signaling. The effect is transient and NK cells may recover after G-CSF clearance, suggesting that G-CSF-mobilized HSCT may benefit both acute GVHD prevention and late-phase GVL promotion in HSCT recipients.
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Acknowledgements
This human subject research study was approved before implementation by the institutional review board of Buddhist Dalin Tzu Chi General Hospital, Taiwan (No. B09604006). The authors thank Miss Ya-Ting Tung and Mr Yi-Hua Jang for assistance with anamnesis integration and sample collection from donors. Dr Elizabeth Coolidge-Stolz, whom we employed, provided editorial assistance during finalization of the manuscript. This study was supported by grant NSC96-2313-B-415-010-MY3 from the National Science Council of the Republic of China, Taipei, Taiwan and grant DTCRD 98-20 from Buddhist Dalin Tzu Chi General Hospital, Chiayi, Taiwan.
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Su, YC., Li, SC., Hsu, CK. et al. G-CSF downregulates natural killer cell-mediated cytotoxicity in donors for hematopoietic SCT. Bone Marrow Transplant 47, 73–81 (2012). https://doi.org/10.1038/bmt.2011.22
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DOI: https://doi.org/10.1038/bmt.2011.22
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